There are three specific aims to this proposal. These are to determine the effects of 1) smoking denicotinized and average nicotine research cigarettes and tobacco smoking equivalent doses of intravenous nicotine (2) and (3) on regional cerebral release of dopamine and endogenous mu opioids in adult male and female tobacco smokers. State of the art positron emission tomography (PET) will be used. To date, data in humans that tobacco smoking releases brain dopamine are very limited and unclear. There are no data that tobacco smoking releases endogenous opioids in human brain. Our preliminary data in six subjects demonstrate proof of concept, but a larger number of tobacco smokers needs to be studied. The functional brain measures will be correlated with venous concentrations of nicotine measured by HPLC. The regional cerebral release of dopamine and endogenous opioids will be measured indirectly as competitive displacement of [11C]raclopride and [11C]carfentinil, respectively. Two separate groups of 36 subjects each will be scheduled for two PET sessions to be performed within a one-week period. All subjects will be run in a similar counterbalanced design. The findings resulting from this research will increase understanding of the effects of nicotine on the brains of normal male and female adult smokers. This information will be important to determine in humans the specific brain areas involved in the reinforcing actions of nicotine and tobacco smoking. This research will provide direct proof of basic neuroscience studies, which indicate nicotine releases neurotransmitters such as dopamine and endogenous opioids. [unreadable] [unreadable] [unreadable]